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Updated: Aug 28, 2025
One-step Metabolomics: Carbohydrates, Organic and Amino Acids Quantified in a Single Procedure
Published on: June 25, 2010
Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns
Álvaro Martín-Rivada1, Ana Cambra Conejero2, Elena Martín-Hernández3
1Sección de Gastroenterología y Nutrición, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
Insights
Elevated C3 levels in newborn screening often lead to false positives. Early diagnosis of propionic acidemia (PA) and methylmalonic acidemia (MMA) is challenging, while maternal vitamin B12 deficiency is common.
Area of Science:
- Biochemistry
- Genetics
- Neonatal Medicine
Background:
- Expanded newborn screening (NBS) aims to detect inborn errors of metabolism (IEMs) early.
- Propionic acidemia (PA), methylmalonic acidemia (MMA), and cobalamin deficiencies (MMAHC) are IEMs detectable by NBS.
- Madrid Region implemented expanded NBS, necessitating evaluation of its effectiveness for these conditions.
Purpose of the Study:
- To report on the diagnosis and follow-up of positive cases for PA/MMA/MMAHC since the implementation of expanded NBS in Madrid.
- To assess the diagnostic yield and challenges associated with NBS for these specific metabolic disorders.
Main Methods:
- Dried blood spots collected 48 hours post-birth.
- Quantification of amino acids and acylcarnitines using MS/MS.
- Biochemical and molecular genetic studies for disease confirmation in referred newborns.
Main Results:
- Over 588,000 infants screened (2011-2020), with 953 referred for abnormal results (192 for elevated C3).
- Confirmed IEMs included 8 PA, 4 MMA, and 7 MMAHC cases.
- Maternal vitamin B12 deficiency was identified in 85 cases, often linked to maternal dietary factors or pernicious anemia.
Conclusions:
- Elevated C3 is a common NBS abnormality, frequently resulting in false positives.
- Presymptomatic diagnosis of PA and some MMA/MMAHC cases remains difficult.
- Maternal vitamin B12 deficiency presents with diverse clinical and biochemical profiles and is treatable.
Objectives:
We present the results of our experience in the diagnosis and follow up of the positive cases for propionic, methylmalonic acidemias and cobalamin deficiencies (PA/MMA/MMAHC) since the Expanded Newborn Screening was implemented in Madrid Region.
Methods:
Dried blood samples were collected 48 h after birth. Amino acids and acylcarnitines were quantitated by MS/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed.
Results:
In the period 2011-2020, 588,793 children were screened, being 953 of them were referred to clinical units for abnormal result (192 for elevated C3 levels). Among them, 88 were false positive cases, 85 maternal vitamin B12 deficiencies and 19 were confirmed to suffer an IEM (8 PA, 4 MMA, 7 MMAHC). Ten out 19 cases displayed symptoms before the NBS results (6 PA, 1 MMA, 3 MMAHC). C3, C16:1OH+C17 levels and C3/C2 and C3/Met ratios were higher in newborns with PA/MMA/MMAHC. Cases diagnosed with B12 deficiency had mean B12 levels of 187.6 ± 76.9 pg/mL and their mothers 213.7 ± 95.0; 5% of the mothers were vegetarian or had poor eating while 15% were diagnosed of pernicious anemia. Newborns and their mothers received treatment with B12 with different posology, normalizing their levels and the secondary alterations disappeared.
Conclusions:
Elevated C3 are a frequent cause for abnormal result in newborn screening with a high rate of false positive cases. Presymptomatic diagnosis of most of PA and some MMA/MMAHC is difficult. Vitamin B12 deficiency secondary to maternal deprivation is frequent with an heterogenous clinical and biochemical spectrum.
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